Interpretive Summary: The influenza pandemic of 1918-19 resulted in the deaths of millions of people worldwide and an estimated 550,000 deaths in the United States. This exceptionally high mortality rate lowered the average life expectancy in the U.S. by almost ten years. The severity of the 1918 pandemic is unprecedented; by comparison, the influenza pandemics of 1957 and 1968 caused substantially less mortality, approximately 70,000 and 34,000 death in the U.S., respectively. The 1918 pandemic was also unusual in that previously healthy adults suffered a disproportionately high rate of mortality. In this work, parts of the 1918 virus was reconstructed and found to be lethal in mice. This suggests an important role for certain proteins in virulence. We further showed that this virus is sensitive to FDA-approved drugs and that growth of viruses are inhibited by these drugs in tissue culture and in the mouse.

Technical Abstract:
The 1918 influenza pandemic caused more than 20 million deaths worldwide. Under biosafety level 3Ag containment, a recombinant influenza virus bearing the 1918 influenza virus hemagglutinin (HA) and neuraminidase (NA) was generated. This virus is highly virulent in mice, pointing to the 1918 HA and 1918 NA proteins as virulence factors. This virus is sensitive to FDA approved NA inhibitors, and prior infection with influenza viruses bearing HA molecules from early or recent human isolates protects against a lethal challenge with the 1918-HA 1918-NA virus. Thus, effective vaccine and antiviral approaches are available for use against such a virus. Further, the exposure of most individuals to the currently circulating H1N1 viruses likely offers some protection against a re-emergent 1918 virus.